Project Summary (Limit 30 lines) Tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR) signaling pathway have emerged as important therapeutics in oncology with a total of nine such VEGFR-TKI having been approved in the last decade. Despite considerable efficacy, VEGFR TKIs are associated with hypertension and other cardiovascular sequalae. Currently, little consensus exists for predictors as well as for preventive and treatment strategies for VEGF-TKI associated hypertension. This proposal is in response to the NIH Funding opportunity announcements (FOA) that encourages collaborative applications that contribute to the identification and characterization of patients at risk of developing cancer treatment-related cardiovascular toxicity. Using the Vanderbilt cardio-oncology program as a platform, we have assembled a team with the goal of understanding the mechanisms of VEGF-TKI associated hypertension and to develop precision preventive and treatment strategies. We hypothesize that interactions between VEGFR and endothelin-1 (ET-1) signaling impact hypertension and vascular dysfunction in VEGF-TKI associated hypertension. In basic studies, we investigate the mechanism by which VEGF signaling regulates ET-1 transcription and expression (aim 1). In correlative clinical and translational studies, we will determine the impact of endothelin receptor antagonism on VEGF-TKI hypertension using approved drugs (aim 2). Finally, we will develop a novel precision risk predictor for VEGF-TKI hypertension with a polygenic, clinical and biomarker predictors (aim 3). Our unique approach addressing the toxicities associated with this class of cancer therapies could have implications for studying cardiac issues that arise from other cancer therapies, especially as these are being combined for use with VEGFR-TKI.